The cell-biological program termed epithelial-mesenchymal transition (EMT) plays a prominent role in carcinoma pathogenesis. In addition to the initial connection made between the EMT program and tumor invasion and dissemination, activation of the EMT program was recently found to induce carcinoma cells to enter into the cancer stem cell (CSC) state, thus greatly enhances the abilities of the carcinoma cells to initiate tumor growth at distant metastatic sites or following cessation of common anti-cancer regimen. Despite the central functions of the EMT program in carcinoma pathogenesis, little is known regarding the nature of the EMT program that is activated during tumor development in vivo, nor about the downstream mediators of the EMT program that subsequently induce and/or maintain the CSC state. The proposed project aims to elucidate the cellular and molecular mechanisms that activate and sustain the EMT program and the resulting CSC state during multi-step carcinoma pathogenesis using breast cancer as the model system. To this end, using genetically engineered reporter mouse lines of EMT-inducing transcription factors (EMT-TFs) in combination with an optimized autochthonous mouse model of metastatic mammary tumor, I have identified the Snail EMT- TF as the major determinant of the breast CSC state. Strikingly, Snail is dispensable for maintaining normal tissue homeostasis of the mammary gland, and depletion of Snail allows selective elimination of mammary tumor stem cells over normal mammary stem cells. For these reasons, I propose to investigate the molecular mechanisms underlying the control of breast CSC state by the Snail-driven EMT program, and to elucidate the signals that induce Snail expression at the first place during tumor development. The aims are (1) To identify the downstream target genes of the Snail-driven EMT program in breast CSCs, and to explore their prognostic and therapeutic values; (2) To investigate the functions of Snail-interacting transcription co-factors in induction and maintenance of the CSC state; and (3) To elucidate the cell-autonomous and non-cell autonomous signals responsible for Snail-activation during multi-step mammary tumor progression.